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Synthesis of 2-spiroindolines from 2-substituted indole derivatives via acid-induced N -acyliminium ion-conjugated diene spirocyclization was demonstrated. This methodology can be used to direct transformations of 2-substituted indole moieties into 3-nonsubstituted-2-spiroindoline skeletons.

The naturally occurring marine alkaloid halichlorine, isolated from the black marine sponge Halichondria okadai Kadota, has been claimed to selectively inhibit the induced expression of vascular cell adhesion molecule-1 (VCAM-1) and might therefore be useful in the treatment of allergic inflammatory diseases and cancer. Stimulated by this intriguing biological profile, as well as the challenging architectural features of halichlorine, a significant amount of work related to the synthesis of this compound has been disclosed. Since the first total synthesis of halichlorine by the Danishefsky group, two other syntheses have been reported by Heathcock and more recently by Clive. The remainder of the many publications in this area have dealt very largely with construction of the azaspirocyclic core system and with formal synthesis reliant on the Danishefsky route.

The purpose of this review is to describe some of our achievements in the total synthesis of the tricyclic marine alkaloids isolated from the ascidians such as fasicularin, lepadiformine, and cylindricine C. The first total synthesis of (±) -fasicularin and (±) -lepadiformine was accomplished employing a stereocontrolled intramolecular hetero-Diels-Alder reaction of an N-acylnitroso moiety to an exocyclic diene. The synthesis of natural (-) -enantiomer of lepadiformine was then undertaken using a highly efficient protocol involving a new variant of an N-acyliminium ion-initiated intramolecular spirocyclization. These syntheses of lepadiformine led to revision of the published structure of the natural product, formerly assigned incorrectly, and established its absolute stereochemistry to be 2R, 5S, 10S, 13S. The developed strategy based on the spirocyclization was also applied to the total synthesis of (+) -cylindricine C and (-) -fasicularin. The ability of fasicularin to damage DNA by acting as an alkylating agent was investigated.

The first successful attempt at synthesizing the 11-membered ring of madangamine alkaloids is described. The synthesis involves intramolecular N,O-acetalization of a cyclohexanone derivative, cross-coupling reaction with (Z)-vinylstannane, and intramolecular reductive amination for elaboration of the 11-membered macrocycle.

A very short and efficient enantioselective total synthesis of the tricyclic marine alkaloids (-)-lepadiformine (3), (+)-cylindricine C (1c), and (-)-fasicularin (4) has been developed utilizing the formyloxy 1-azaspiro[4.5]decane 5 as a common intermediate. The key strategic element for the synthesis was the formic acid-induced intramolecular conjugate azaspirocyclization, which proved to be a highly efficient and stereoselective way to rapid construction of the 1-azaspirocyclic substructure of these natural products in a single operation. Thus, the common intermediate 5, synthesized in two steps with 70% overall yield starting from the known (S)-N-Boc-2-pyrrolidinone 7 via the conjugate spirocyclization using an acyclic ketoamide 6, was utilized for the concise and stereoselective total synthesis of (-)-lepadiformine (3), which was accomplished in seven steps with 45% overall yield from 5 (31% yield from 7). The developed strategy based on the conjugate spirocyclization was also applied to the stereoselective total synthesis of (+)-cylindricine C (1c), which was achieved in 10 steps from 5 in 18% overall yield (12% yield from 7). Further application of this approach using 5 led to the synthesis of (-)-fasicularin (4), wherein an extremely efficient method for the introduction of the thiocyanato group via an aziridinium intermediate at the last step was developed. Thus, the highly efficient first enantioselective total synthesis of (-)-fasicularin was accomplished in nine steps with an overall yield of 41% from 5 (28% yield from 7).

The first total syntheses of new monoterpene alkaloids (-)-incarvilline, (+)-incarvine C, and (-)-incarvillateine, corresponding to the natural enantiomers, have been accomplished. The strategy for the synthesis of these natural products utilized 6-epi-incarvilline as a common precursor, which was assembled by a three-component coupling reaction using (4S)-4-siloxy-2-cyclopenten-1-one to construct an appropriately trisubstituted cyclopentanone, followed by ring closure to the cis-perhydro-2-pyrindine skeleton by means of a reductive Heck-type reaction. Furthermore, topochemically controlled [2 + 2] photodimerization of cinnamic acid derivatives in the solid state for the stereospecific construction of a 1,2,3,4-tetrasubstituted cyclobutane ring was also investigated as a means to access (-)-incarvillateine.

A new approach to synthesize the madangamine core structure is described. The synthesis involves intramolecular N,O-acetalization of the keto-aminophenol which allows rapid construction of the 2-azabicyclo[3.3.1]nonane skeleton with a quaternary carbon center at C4. This strategy also demonstrates the utility of such approach in the stereoselective construction of the central diazatricyclic core found in the madangamine alkaloids.

A stereoselective total synthesis of (+)-cylindricine C has been achieved starting with ( S )- N -Boc-2-pyrrolidinone. The key elements of this synthesis involve the sequence of reactions including BF 3 -mediated addition of the allyl Grignard reagent to the cyclic imine, spirocyclization via enamine formation, and intramolecular Michael addition to form the tricyclic core.

[reaction: see text] The enantioselective total syntheses of (+)-azimine and (+)-carpaine have been developed, starting with (S)-1,2,4-butanetriol as a single source of chirality. The key common feature in these syntheses involves stereoselective intramolecular hetero-Diels-Alder reaction of an acylnitroso compound. The critical macrocyclic dilactonization of the N-Cbz derivatives of azimic acid and carpamic acid was efficiently achieved by using the Yamguchi macrocyclization conditions.

An enantioselective total synthesis of NK-1 receptor antagonists, (+)-CP-99,994 and (+)-CP-122,721, is described. The key steps are diastereoselective addition of vinyllithium to a chiral benzaldehyde oxime ether and diastereoselective borane reduction of a cyclic oxime ether.

A versatile convergent approach for preparing the pumiliotoxin alkaloids has been developed employing a Pd(0)-catalyzed cross-coupling reaction between homoallylic organozincs and vinyl iodides, which led to the asymmetric total synthesis of (+)-pumiliotoxins A ( 1 ) and B ( 2 ). The ( Z )-alkylideneindolizidine, which is a common organic part of the organozinc reagents in this approach, was synthesized with a high degree of stereocontrol upon using HfCl 4 -mediated addition of the allenylsilane to ( S )-2-acetylpyrrolidine. The ( Z )-iodoalkylideneindolizidine ( 31 ) thus obtained as an advanced common intermediate was converted into the homoallylzinc chloride derivative 32 , which underwent homoallyl-vinyl cross-coupling with the ( E )-vinyl iodide ( 13 ) using Pd(PPh 3 ) 4 catalyst to afford the 1,5-diene product 33 . Subsequent deprotection provided (+)-pumiliotoxin A. On the other hand, 31 was transformed into the homoallyl- tert -butyl zinc intermediate 39 , which was cross-coupled with the ( E )-vinyl iodide ( 36 ) in the presence of the Pd(0) catalyst. The resulting 1,5-diene product 40 underwent subsequent deprotection to afford (+)-pumiliotoxin B.

Chiral (E)-arylaldehyde oxime ethers, prepared using (R)-1-phenyl-1,2-ethanediol as a chiral auxiliary, undergo nucleophilic addition with methyllithium to give diastereomerically enriched O-alkyl hydroxylamines which, after reductive N O bond cleavage, lead to the corresponding (R)-1-(aryl)ethylamines. This methodology has been applied to the enantioselective synthesis of a new type of arylalkylamine calcimimetics (R)-(+)-NPS R-568 and its thio analogue.

The first total synthesis of tricyclic marine alkaloids (±)-fasicularin (2) and (±)-lepadiformine (5) was accomplished. The key common strategic element for the synthesis is the stereocontrolled intramolecular hetero-Diels−Alder reaction of an N-acylnitroso moiety to an exocyclic diene with or without bromine substitution to control the syn-facial or anti-facial selectivity, respectively, leading to the trans- or cis-fused decahydroquinoline ring systems 21 or 39 involving the simultaneous introduction of the nitrogenated quaternary center in a single step. On further elaboration of the six-membered or five-membered ring A, the trans-fused adduct 21 provided either (±)-fasicularin (2) or (±)-lepadiformine (5). The hydrochloride salt of synthetic (±)-5 was found to be identical with the isolated natural sample of lepadiformine; however, the tricyclic amino alcohol 4 having the proposed structure of lepadiformine in a nonzwitterionic form, derived from the cis-fused adduct 39, was found to be different from...

A stereocontrolled approach to the proposed structure of lepadiformine has been achieved employing an intramolecular hetero Diels–Alder reaction of an N-acylnitroso compound, in which syn-face selectivity was controlled. The NMR data of the product synthesized based on this approach is not identical with those reported for natural lepadiformine. Thus, the proposed structure for natural lepadiformine must be revised.

New strategies for the syntheses of the pumiliotoxin (PTX) A dendrobatid alkaloids have been developed which are based on palladium-catalyzed carbonylation, palladium-catalyzed cross-coupling reaction, and nickel-chromium-mediated cyclization. Application of these methodologies to the asymmetric total syntheses of (-) -PTX 209F, (-) - PTX 225F, (+) -PTX A, (+) -allo-PTX 267A, (+) -allo-PTX 339A, and (+) -homo-PTX 223G is described.

The first asymmetric total synthesis of a new coccinellid alkaloid (−)-adalinine has been achieved, based on the construction of a 2-piperidone framework with an asymmetric quaternary center at the C-6 position, which was performed by Lewis acid-induced allylation of the cyclic N-acyl-N,O-acetal incorporating the chiral aminophenol auxiliary. This synthesis allowed the absolute stereostructure of natural (−)-adalinine to be assigned as R.

An asymmetric total synthesis of (−)-epibatidine (1), isolated from the skin of the Ecuadorian poison frog, Epipedobates tricolor, of the family Dendrobatidae, has been achieved by virtue of the development of asymmetric hetero Diels−Alder (D−A) cycloaddition with an N-acylnitroso dienophile bearing the optically active 8-arylmenthol as a chiral source. Thus, in situ oxidation of the hydroxamic acid ent-12f incorporating the (1S,2R,5S)-8-(2-naphthyl)menthyl auxiliary was performed using the Swern conditions to produce the acylnitroso dienophile, which reacted at once with 2-chloro-5-(1,5-cyclohexadienyl)pyridine (7) to provide the (1S,4R)-meta-aza cycloadduct 24 as a major diastereoisomer. The observed facial diastereoselectivity is consistent with a transition-state model with the naphthyl group in “stacked” position and with the acylnitroso group in the s-cis conformation, wherein π attractive interaction between the naphthyl and nitrosocarbonyl groups may contribute to facial control. Compound 24 under...

An enantioselective approach to (−)-epibatidine based on asymmetric hetero Diels-Alder cycloaddition with an N -acylnitroso dienophile bearing 8-(2-naphthyl)menthol as a chiral source, wherein π-π stacking interaction between the naphthyl and nitrosocarbonyl groups may contribute to facial control, is described.

A new practical route for the first total synthesis of (+)-homopumiliotoxin 223G is described, in which the palladium-catalyzed carbonylation of the vinyl iodide, leading to efficient construction of the quinolizidine nucleus incorporating the (Z)-alkylidene side chain, is the key strategic element. Another key feature of this synthesis involves the Lewis acid-induced chelation-controlled propargylation using the allenylsilane with complete diastereoselectivity.

Et 2 AlCl-mediated nucleophilic alkylation with Grignard reagents on chiral perhydropyrido[2,1- b ]pyrrolo[1,2- d ][1,3,4]oxadiazine has proved to proceed via an S N 2 mechanism at low temperatures (below −80 °C) with high to excellent inversive stereoselection, while, at an elevated temperature, hydrazonium ions are formed preferentially leading to retentive stereoselection. This methodology provides useful access to enantioselective preparation of 2-substituted piperidines and is used for asymmetric synthesis of (+)-coniine.

Upon treatment with catalytic Pd2(dba)3•CHCl3 in the presence of AcOH, the enyne compounds were subjected to hydropalladation followed by cyclic carbopalladation to form the homoallylpalladium complexes, which subsequently underwent in situ Stille type cross coupling with various vinyltin reagents to give the cyclized products bearing allyl appendages. © 1997 Elsevier Science Ltd.

Lewis acid-promoted conjugate addition reaction of an allylsilane to a series of the chiral 8-arylmenthol-derived N -acyl-2,3-dihydro-4-pyridones leads to the 2-allyl-4-piperidones with moderate to high levels of asymmetric induction, indicating π-stacking contribution to chirality control. This methodology was applied to the asymmetric synthesis of (−)- N -methylconiine.

Hydroxyl-promoted reductive cyclization of enyne compounds catalyzed by Pd(OAc) 2 -BBEDA was explored and found to effect constructing the pyrindine framework with the alkylidene appendage. This methodology was applied to the stereoselective synthesis of (−)-4a,5-dihydrostreptazolin.

Lewis acid-mediated nucleophilic alkylation of the chiral [6,3a,4]oxadiaza-indano[5,4-α]isoquinoline derivatives with various organometallic reagents leads to highly enantioselective synthesis of 1-alkyl substituted tetrahydroisoquinolines. This methodology was applied to the asymmetric synthesis of (−)-salsolidine and (+)- O -methylarmepavine.

The natural Z isomer of (+)-streptazolin (1), isolated from cultures of Streptomyces viridochromogenes, was synthesized in an optically pure form for the first time on the basis of a palladium-catalyzed enyne bicyclization approach in 12 steps and 4.3% overall yield from (3R,4R)-3,4-bis(benzyloxy)succinimide (5). The requisite enyne 13 for palladium-catalyzed bicyclization was prepared from 5 via N-acyliminium ion cyclization of the acetoxy lactam 9, partial reduction of 10 with DIBALH−BuLi, and conversion to the dibromo olefin 12. The best result in the palladium-catalyzed bicyclization was obtained when treated with 30 mol % Pd(OAc)2 and N,N ‘-bis(benzylidene)ethylenediamine (BBEDA) as the ligand in benzene at reflux, thus affording a 93:7 mixture of the 1,2,4a,7a,6,7-hexahydro-5H-1-pyrindine (Z)-14 along with its isomerized product (Z)-15 in 84% total yield. The isomerization of the 1,4-diene in (Z)-14 to the 1,3-diene was achieved by treatment with triiron dodecacarbonyl to generate the stable tricarb...

The macrocyclic spermidine alkaloid (−)-oncinotine (1), isolated from Oncinotis nitida (Apocynaceae), was synthesized enantioselectively for the first time based on intramolecular iminium ion cyclization utilizing enantiomerically pure (2S)-N-[(benzyloxy)carbonyl]-2-piperidineacetaldehyde (8) as a chiral starting material. The required 8 was derived from the erythro adduct 16, which was obtained by diastereoselective 1,3-dipolar cycloaddition between 2,3,4,5-tetrahydropyridine 1-oxide (4) and (3S)-3-[(tert-butyldiphenylsilyl)oxy]-4-methyl-1-pentene (15). Wittig condensation of 8 with [8-(methoxycarbonyl)octyl]triphenylphosphonium iodide (21) followed by saponification provided the chiral piperidine moiety 23, which was coupled with the N-propyl-1,4-butanediamine segment 29 by using diethoxyphosphoryl cyanide in the presence of triethylamine to afford the tertiary amide 30. Conversion of 30 to the aldehyde 34 via desilylation and Swern oxidation, followed by hydrogenation over a palladium hydroxide catalys...

A chiral approach to (–)-pumiliotoxin C based on an aqueous intramolecular acylnitroso Diels–Alder reaction is described. Upon treatment of the (S)-1,3-diene hydroxamic acid 19, available from L-malic acid, with Pr4NIO4 under the aqueous conditions, the in situ generated acylnitroso compound 19 was subjected to intramolecular [4 + 2] cycloaddition to yield the trans-1,2-oxazino lactam 21 with significantly increased diastereoselectivity in comparison with the same cycloaddition conducted in a chloroform solution. Subsequent addition of the propyl side chain was achieved by means of a tandem Grignard reaction–NaBH3CN reduction in a completely stereocontrolled manner. The bicyclic 1,2-oxazine 26 thus obtained was converted into the all-cis-decahydroquinoline 34 by sequential reductive N–O bond cleavage, aldol condensation of the diketone 31 and hydrogenation of the octahydroquinolone 33. Clemmensen reduction of 34, followed by LiAlH4 reduction, provided a ca. 2 : 1 epimeric mixture of α-methyl and β-methyl isomers 36 and 37, and subsequent debenzylation converted the major isomer 36 into 5-epi-pumiliotoxin C 2. On the other hand, 34 underwent LiAlH4 reduction followed by Swern oxidation to afford a 1.2 : 1 epimeric mixture of the decahydroquinolones 39 and 41. Equilibrium control of this epimeric mixture by prolonged heating with Zn(OTf)2 followed by treatment with ethane-1,2-dithiol resulted in the exclusive formation of the thermodynamically more stable β-methyl epimer 43 as a single isomer, which was converted into (–)-pumiliotoxin C 1 by desulfurization and debenzylation.

Nucleophilic addition of carbon nucleophiles and metal hydride reagents to hydrazonium salts modified by optically active 2-substituted pyrrolidine auxiliaries leads to highly enantioselective synthesis of 1-substituted tetrahydroisoquinolines. This methodology was applied to asymmetric synthesis of the title isoquinoline alkaloids.

In this review our own work on the development of chiral approaches to nitrogenous natural products based on a methodology involving conformational control in the transition states under nonchelation conditions has been presented. On 1, 2-asymmetric induction in the reaction of achiral reagents at the diastereotopic faces of a prochiral C=X (X=C, N, O etc.) group adjacent to an asymmetric carbon atom, the increased π-facial selectivity is brought about by conformational fixation of the single bond between the asymmetric center and the prochiral reaction center. Apart from cyclic chelation control, the useful ways to achieve this is to utilize the conformational restraints imposed by Cram-Felkin-Anh mode of nucleophilic addition, inside alkoxy effect, and allylic 1, 3-strain. Employing these nonchelation methodologies for controlling the stereochemistry of acyclic systems, we have succeeded in the enantiopure preparation of nitrogenous natural products including alkaloids, azasugars, and antibiotics.

Conformationally constrained spirofuropyridine analogues of epibatidine, syn-2 and anti-2 , in which the 7-azabicyclo[2.2.1]heptane system and the 2-chloropyridine ring are held rigidly with the shorter and longer N–N distances, respectively, were synthesized from N-Boc-7-azabicyclo[2.2.1]heptan-2-one. The preliminary binding studies suggested that syn-2 has stronger binding affinity for nAChRs than anti-2 .

A chiral approach to (−)-pumiliotoxin C via a stereoselective intramolecular hetero Diels-Alder reaction of a chiral acylnitroso compound performed in an aqueous medium is described.

Macrodiolide (−)-vermiculine has been synthesized via intramolecular Mitsunobu reaction utilizing a C2 symmetrical diepoxide chiral synthon.

A new noncarbohydrate-based enantioselective approach to (-)-swainsoni- ne (1) is described, in which the aqueous intramolecular Diels-Alder reaction of a chiral acylnitroso diene has been employed as a key reac- tion. The intramolecular cycloaddition of the chiral hydroxamic acid (9), available from D-malic acid in (10) steps, with Pr 4 NIO 4 was con- ducted under the conventional nonaqueous conditions using CHCl 3 as a solvent, where upon intermediacy acylnitroso compound (10) cyclized spontaneously to give the trans- and cis-1,2-oxazinolactams (11) and (12) with a low diastereoselction of 1.3:1 in 76% combined yield. When the corresponding reaction was performed in water, it led to signifi- cant enhancements of trans selectivity of 4.1:1 as well as combined yield (89%). The trans adduct (11) was subjected to reductive N-O bond cleavage followed by diastereoselective hydroxylation with OsO 4 to provide the 1,2-glycol (21), which was then converted to the amino alcohol (25). Intramolecular cyclodehydration of (25) with CBr 4 /PPh 3 - /Et 3 N and subsequent deprotection furnished (-)swainsonine

In an aqueous medium, intramolecular hetero Diels-Alder cycloadditions of the chiral acylnitroso compounds, generated from the chiral hydroxamic acids by in situ periodate oxidation, shows a pronounced enhancement of the trans selectivity compared with the results obtained by employing nonaqueous conditions.

A remarkably high regio- and stetreoselective approach for the syntheses of (+)-allopumiliotoxin alkaloids 267A and 339A based on intramolecular nickel(II)/chromium( 11)-mediated ring closure has been developed. South American poison-dart frogs of the family Dendrobatidae have been a rich source of various structurally unique alkaloids. Virtually all of these alkaloids possess high pharmacological activity on nerve and muscle. After the early discovery of four classes of dendrobatid alkaloids that are of the pumiliotoxin C class, the histrionicotoxins, gephyrotoxins, and batrachotoxins, new members of the pumiliotoxin A class and their allo series were isolated and structurally defined.* The latter subclass of alkaloids, the allopumiliotoxins, is a group of hydroxy congeners of the pumiliotoxin A class and they are the most complex members of the pumiliotoxin A alkaloid group.3 For several years, research efforts in our laboratory have been directed toward the development of chiral methods for the total syntheses of dendrobatid alkaloids.4 This article is concerned with the highly regio- and stereocontrolled approach to (+)-allopumiliotoxins 267A (1) and 339A (2).

An efficient method for the stereoselective synthesis of tetracyclic spirolactams is presented.

The first total synthesis of (+)-decarestrictine L, a member of a new family of inhibitors of cholesterol biosynthesis, has been achieved utilizing a C 2 symmetrical diepoxide chiral synthon. The approach involves the construction of the tetrahydropyranyl nucleus by fully stereocontrolled intramolecular 1,4-conjugate addition.

Macrodiolides (−)-pyrenophorin and (−)-pyrenophorol have been synthesized utilizing a C 2 symmetric ( R,R )-diepoxide as a common enantiopure chiral building block.

Facile routes for the preparation of an optically active allylic ether bearing the tert-butyl group at an allylic chiral center, i. e. 2-(benzyloxy)-3,3-dimethyl-1-pentene, in both (R)- and (S)-enantiomeric forms, which are expected to be promising, efficient dipolarophiles in highly stereoselective asymmetric nitrone cycloaddition, have been developed, utilizing commercially available L-tert-leucine and (R)-pantolactone, respectively, as chiral precursors

Stereoselective total syntheses of (+)-castanospermine (1) and (+)-1-epicastanospermine (2) and their 1O-acyl derivatives 3-5 have been achieved via a noncarbohydrate-based approach utilizing allylic alcohol 9 as a common chiral building block. Epoxide 10, prepared from 9, underwent regio- and stereoselective ring opening with Et 2 AIN(CH 2 Ph) 2 to give amino alcohol 11, which was converted to aldehyde 15 in four steps. The aldol reaction of 15 with lithio ethyl acetate was predominantly anti selective and generated α-hydroxy ester 16 by a nonchelate Felkin-Anh pathway

We have developed an alternative route to the azatricyclic core skeleton of FR901483 based on vinylation at the bridgehead position of 2-azabicyclo[3.3.1]nonane via an anti-Bredt iminium ion using vinylaluminum reagents.